Cleavage-stage or blastocyst-stage embryo biopsy has no impact on growth and health in children up to 2 years of age.

BACKGROUND: Studies show conflicting results on neonatal outcomes following embryo biopsy for PGT, primarily due to small sample sizes and/or heterogeneity in the timing of embryo biopsy (day 3; EBD3 or day 5/6; EBD5) and type of embryo transfer. Even fewer data exist on the impact on children's health beyond the neonatal period. This study aimed to explore outcomes in children born after EBD3 or EBD5 followed by fresh (FRESH) or frozen-thawed embryo transfer (FET). METHODS: This single-centre cohort study compared birth data of 630 children after EBD3, of 222 EBD5 and of 1532 after non-biopsied embryo transfers performed between 2014 and 2018. Follow-up data on growth were available for 426, 131 and 662 children, respectively. RESULTS: Embryo biopsy, either at EBD3 or EBD5 in FET and FRESH cycles did not negatively affect anthropometry at birth, infancy or childhood compared to outcomes in non-biopsied FET and FRESH cycles. While there was no adverse effect of the timing of embryo biopsy (EBD3 versus EBD5), children born after EBD3 followed by FET had larger sizes at birth, but not thereafter, than children born after EBD3 followed by FRESH. Reassuringly, weight and height gain, proportions of major congenital malformations, developmental problems, hospital admissions and surgical interventions were similar between comparison groups. CONCLUSION: Our study indicated that neither EBD3 nor EBD5 followed by FRESH or FET had a negative impact on anthropometry and on health outcomes up to 2 years of age.

Impact of embryo vitrification on children's health, including growth up to two years of age, in comparison with results following a fresh embryo transfer.

OBJECTIVE: To assess health outcomes, including growth up to 2 years of age, in children born after embryo vitrification in comparison with children born after fresh embryo transfer. DESIGN: A prospective cohort study. SETTING: A single-center university hospital. PATIENT(S): Singletons born after the transfer of vitrified or fresh embryos, either at the cleavage or blastocyst stage between 2014 and 2018, were included. INTERVENTION(S): Multiple linear and logistic regression analyses were used to study the association between outcomes after vitrified versus fresh embryo transfer, controlling for neonatal, treatment, and maternal characteristics. Subgroup analysis according to cycle protocol (hormone replacement vs. natural cycle) and strategy (freeze-all vs. previous fresh cycle) was also performed. MAIN OUTCOME MEASURE(S): Measurements at birth and growth in infancy and childhood, as well as health outcomes, including congenital malformations, interventions, medication use, and hospitalizations are reported. RESULT(S): Birth characteristics were available for 1237 and 2063 children born after embryo vitrification and fresh embryo transfer, respectively. Follow-up data were available for 582 and 757 children at infancy and for 233 and 296 children at 2 years, respectively. Birthweight, height, and head circumference SD scores of children born after embryo vitrification were higher than children born after fresh embryo transfer, even after adjustment for neonatal, treatment, and maternal characteristics. In infancy, weight and height SD scores were larger for children born after embryo vitrification, but not after adjustment for covariates. In childhood, no differences in anthropometry were observed between the groups. Weight and height gain from birth to infancy and from infancy to early childhood were comparable between the groups. Comparable rates of severe developmental problems, hospital admissions, surgical interventions, and of chronic medication use were observed up to the age of 2 years. Subgroup analysis showed that growth parameters were not affected by the cycle protocol or strategy at any age. CONCLUSION(S): Our study indicated that embryo vitrification is associated with higher birthweight, even after controlling for confounders. However, in early childhood, anthropometry and weight and height gain was not different in children born after vitrified or fresh embryo transfer.

Erratum to: Health of 2-year-old children born after vitrified oocyte donation in comparison with peers born after fresh oocyte donation.

[This corrects the article DOI: 10.1093/hropen/hoab002.].

Health of 2-year-old children born after vitrified oocyte donation in comparison with peers born after fresh oocyte donation.

STUDY QUESTION: Does oocyte vitrification adversely affect the health of 2-year-old children compared with peers born after use of fresh oocytes in a donation programme? SUMMARY ANSWER: The growth and health of 2-year-old children born after oocyte vitrification are similar to those of peers born after use of fresh oocytes. WHAT IS KNOWN ALREADY: Although oocyte vitrification is a well-established procedure in ART, the evidence on its safety for offspring is limited. Currently, no disadvantageous effects of oocyte vitrification have been shown in terms of obstetric and neonatal outcome. However, no data beyond the neonatal period are available to date. STUDY DESIGN SIZE DURATION: A combined retrospective and prospective observational study was performed in a tertiary reproductive centre. The retrospective data were available in our extensive database of children born after ART. Donor cycles with an oocyte retrieval between January 2010 and March 2017 and a fresh embryo transfer resulting in the livebirth of a singleton were selected from the established oocyte donation programme. Fresh or vitrified oocytes were used in the donor cycles and all pregnancies in oocyte recipients were achieved after ICSI. Only children residing in Belgium were eligible for follow-up. PARTICIPANTS/MATERIALS SETTING METHODS: Biometric and health parameters of 72 children born after oocyte vitrification were compared with those of 41 children born after use of a fresh oocyte. Data were collected by means of questionnaires and physical examinations at the age of 21-30 months. The primary outcome measures were anthropometry and health at 2 years of age. MAIN RESULTS AND THE ROLE OF CHANCE: Length, weight, BMI, head circumference, left arm circumference and waist circumference at the age of 2 years were comparable between the vitrification and fresh group, also after adjustment for treatment, and maternal and neonatal characteristics (all P > 0.05). Health of the children in terms of hospital admission and surgical intervention rates were comparable between the vitrification and fresh group (both P > 0.05). LIMITATIONS REASONS FOR CAUTION: Although the current study is the largest series describing health parameters beyond the neonatal period, the small numbers still preclude definite conclusions. WIDER IMPLICATIONS OF THE FINDINGS: This study provides the first evidence indicating that oocyte vitrification does not adversely affect the growth and health of offspring beyond the neonatal period. STUDY FUNDING/COMPETING INTERESTS: This study was supported by Methusalem grants and by grants from Wetenschappelijk Fonds Willy Gepts, all issued by the Vrije Universiteit Brussel. All co-authors declared no conflict of interest in relation to this work. Both the Centre for Reproductive Medicine and the Centre for Medical Genetics from the UZ Brussel have received several educational grants from IBSA, Ferring, MSD and Merck for either research on oocyte vitrification or for establishing the database for follow-up research and organizing the data collection.

Multiple vitrification-warming and biopsy procedures on human embryos: clinical outcome and neonatal follow-up of children.

STUDY QUESTION: Does double vitrification and warming of human blastocysts having undergone biopsy once or twice have an impact on the clinical outcome? SUMMARY ANSWER: The clinical pregnancy rate obtained with double vitrification single biopsy blastocysts was comparable to that obtained with single vitrification single biopsy blastocysts in our center in the same time period (46%; 2016-2018), whereas that obtained with double-vitrified double-biopsied blastocysts seemed lower and will need further study. WHAT IS KNOWN ALREADY: Genetic testing on cryopreserved unbiopsied embryos involves two cryopreservation procedures. Retesting of failed/inconclusive-diagnosed blastocysts inevitably involves a second round of biopsy and a second round of vitrification as well. To what extent this practice impacts on the developmental potential of blastocysts has been studied to a limited extent so far and holds controversy. Additionally, the obstetrical/perinatal outcome after the transfer of double-vitrified/single or double-biopsied blastocysts is poorly documented. STUDY DESIGN, SIZE, DURATION: This retrospective observational study included 97 cycles of trophectoderm biopsy and preimplantation genetic testing (PGT) on vitrified-warmed embryos followed by a second round of vitrification between March 2015 and December 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: In 36 warming cycles, no biopsy was performed on the embryos before the first vitrification (single biopsy group). In 61 warming cycles, the embryos had been biopsied on Day 3 (n = 4) or on Day 5/6 (n = 57) before the first vitrification (double biopsy group). A second biopsy was mostly indicated in cycles of failed or inconclusive diagnosis at the first biopsy. Two cycles involved a more specific mutation test for X-linked diseases on male embryos and one cycle involved testing for a second monogenic indication supplementary to a previously tested reciprocal translocation. Post-warming suitability for biopsy, availability of genetically transferable embryos and clinical outcome of subsequent frozen-thawed embryo transfer (FET) cycles were reported. Neonatal follow-up of the children was included. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 91 cleavage-stage embryos and 154 blastocysts were warmed, of which 34 (37.4%) and 126 (81.8%), respectively, were of sufficient quality to undergo trophectoderm biopsy and were subsequently vitrified for a second time. Out of these, 92 underwent biopsy for the first time (single biopsy), whereas 68 underwent a second biopsy (double biopsy). After diagnosis, 77 blastocysts (48.1%) were revealed to be genetically transferable (44 in the single biopsy group and 33 in the double biopsy group). In 46 warming cycles, 51 blastocysts were warmed and 49 survived this second warming procedure (96.0%). Subsequently, there were 45 FET cycles resulting in 27 biochemical pregnancies and 18 clinical pregnancies with fetal heartbeat (40.0% per FET cycle: 44.0% in the single biopsy group and 35.0% in the double biopsy group, P = 0.54). Thirteen singletons were born (eight in the single biopsy group and five in the double biopsy group), while three pregnancies were ongoing. A total of 26 embryos (13 in each group) remain vitrified and have the potential to increase the final clinical pregnancy rate. The neonatal follow-up of the children born so far is reassuring. LIMITATIONS, REASONS FOR CAUTION: This is a small retrospective cohort, thus, the implantation potential of double vitrification double biopsy blastocysts, as compared to double vitrification single biopsy blastocysts and standard PGT (single vitrification, single biopsy), certainly needs further investigation. Although one could speculate on birthweight being affected by the number of biopsies performed, the numbers in this study are too small to compare birthweight standard deviation scores in singletons born after single or double biopsy. WIDER IMPLICATIONS OF THE FINDINGS: PGT on vitrified-warmed embryos, including a second vitrification-warming step, results in healthy live birth deliveries, for both single- and double-biopsied embryos. The neonatal follow-up of the 13 children born so far did not indicate any adverse effect. The present study is important in order to provide proper counseling to couples on their chance of a live birth per initial warming cycle planned and concerning the safety issue of rebiopsy and double vitrification. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.